Psychedelic neuroplasticity of cortical neurons lacking 5-HT2A receptors

Classic psychedelics can strengthen connections in the retrosplenial cortex, a brain region important for memory and spatial orientation that is impaired in Alzheimer's disease, even though its neurons lack the serotonin 2A receptors thought necessary for such effects. Using a new genetic tool in mice, the research shows that this strengthening depends on presynaptic serotonin 2A receptors on incoming nerve fibers from the anterior thalamus, not on the postsynaptic receptors of the retrosplenial cortex itself. The finding suggests psychedelics may have broader therapeutic potential than currently recognized, possibly aiding conditions like Alzheimer's disease and post-traumatic stress disorder by boosting retrosplenial circuit function.

Study at a glance

Abstract

Classical psychedelic drugs show promise as a treatment for major depressive disorder and related psychiatric disorders. This therapeutic efficacy stems from long-lasting psychedelic-induced neuroplasticity onto prefrontal cortical neurons and is thought to require the postsynaptic expression of serotonin 2A receptors (5-HT_2AR). However, other cortical regions such as the granular retrosplenial cortex (RSG) – important for memory, spatial orientation, fear extinction, and imagining oneself in the future, but impaired in Alzheimer’s disease – lack 5-HT_2AR and are thus considered unlikely to benefit from psychedelic therapy. Here, we show that RSG pyramidal cells lacking postsynaptic 5-HT_2A receptors still undergo long-lasting psychedelic-induced synaptic enhancement. A newly engineered CRISPR-Cas-based conditional knockout mouse line reveals that this form of psychedelic-induced retrosplenial plasticity requires presynaptic 5-HT_2A receptors expressed on anterior thalamic axonal inputs to RSG. These results highlight a broader psychedelic therapeutic utility than currently appreciated, suggesting potential for augmenting RSG circuit function in Alzheimer’s disease, post-traumatic stress disorder, and other neuropsychiatric conditions, despite the lack of postsynaptic 5-HT_2A receptors.